1,3-benzoxazine - 2:4 - dione and pharmacologically acceptable alkali metal salts thereof as analgesics



United States Patent 3,443,014 1,3-BENZOXAZINE 2:4 DIONE AND PHARMA-COLOGICALLY ACCEPTABLE ALKALI METAL SALTS THEREOF AS ANALGESICS LeslieFrederick Wiggins, Wargrave, England, assiguor to Aspro-NicholasLimited, Slough, England, a British company No Drawing. Filed July 21,1961, Ser. No. 125,647

Int. Cl. A61k 27/00 U.S. Cl. 424-248 7 Claims This invention relates tonew pharmaceutical preparations and their use in medicine.

It has been found that the compound 1:3-benzoxazine- 2:4-dione exhibitshypnotic, tranquillising and analgesic activity and is non-gastricirritant, and clinical trials have shown that the compound may be usedfor the relief of pain in human patients suffering from headache orrheumatic pain. The compound has been found to be .a quick-actinganalgesic when given by the oral route.

The 1:3-benzoxazine-2z4-dione forms alkali metal salts, such as thesodium salt, which may be employed in place of the dione itself.

The toxicity of the compound is such that doses of up to 1000 milligramsmay be administered orally say three times a day, whereas its activityis such that doses as low as 10 milligrams each may be employed.

The present invention provides a method of treating a person sufferingfrom various types of pain which includes the step of administering tothat person at least one dose of from 10* to 1000 milligrams of at leastone analgesic compound selected from the class consisting of 1:3-benzoxazine-2r4-dione and pharmacologically acceptable alkali metalsalts thereof.

In accordance with the invention, there is also provided apharmaceutical preparation in dosage unit form comprising 1z3benzoxazine-2z4-dione or a pharmacologically acceptable alkali metalsalt thereof as the active component, together with one or more solid orliquid pharmaceutical diluents or carriers.

The dosage unit may contain from 10 to 500, or even 1000, milligrams ofthe active component. Preferably, the content thereof is from to 200milligrams or, more advantageously, between 40 and 120 milligrams. -Inpractice, the dosage may well be 50' or 100 milligrams and it istherefore preferred to provide tablets or other dosage units eachcontaining 50 or 100 milligrams of the 1:3- benzoxazine-Z 4-dione.

The dosage unit of the pharmaceutical preparations of the presentinvention may exist in any of the customary pharmaceutical forms, suchas for example tablets, capsules, cachets, packaged powders, pills,ampouled solutions for parenteral administration, suppositories forrectal administration and suspensions for oral administration, althougha form adapted for oral administration, especially tablets, ispreferred.

The percentage of active component in the pharmaceutical preparation maybe varied, providing that the preparation, irrespective of theparticular form in which the dosage unit may exist, contains suflicientof the active component to have the required pharmacological effect. Ingeneral, the preparation should normally contain at least 0.25% byweight of the active component when required for oral administration andat least 0.1% by; weight of the active component when required foradministration by injection. If desired, several dosage unit forms maybe administered at about the same time.

Some examples of the pharmaceuticaldiluents or carriers which may beemployed in the pharmaceutical preparations of the invention are sugarssuch as lactose and sucrose; maize starch; talc; magnesium stearate;calcium phosphate; liquid parafiin; oil of theobrom-a; citric acid;

Patented May 6, 1969 syrup B.P.; methyl cellulose; methyl and propylhydroxybenzoate; and polyoxyethylene sorbitan monolaurate.

If desired, the pharmaceutical preparations may contain, in addition tothe active component 1:3-benzoxazine- 2:4-dione, one or more otherpharmacologically active substances, for example acetylsalicylic acid,phenacetin, caffeine, codeine, salicylamide, phenazone, iso-propylphenazone, paracetamol(N-acetyl-p-aminophenol) or amidopyrine. They may,for example, contain phenacetin and also caffeine and/or codeine.

The alkali metal salts of 1:3-benzoxazine-2z4-dione which may beemployed in accordance with the present invention are novel compounds.By way of example, the sodium salt is a white crystalline salt whichdoes not melt up to 310 C. and which is soluble in water to at least10%, a solution of a concentration of 10% exhibiting a pH of 8.3. Thissalt may be made by adding to a boiling solution of 25 g. of4-hydroxycoumarin in 300 ml. of dry ethanol a solution obtained bydissolving 7.0 g. of sodium metal in 100 ml. absolute ethanol, Aprecipitate forms and on cooling is filtered off and washed withalcohol. After drying, its weight is 23.5 g. Sodium found 12.4%;calculated 12.5%.

To illustrate the invention, the following specific examples ofpharmaceutical preparations in accordance with the invention will now begiven.

Example 1 Tablets were prepared from the following:

G. 1:3-benzoxazine-2:4-dione 400 Lactose Maize starch, dried 119Magnesium stearate 1 The 1:3-benzoxazine-224-dione, lactose and 89 g. ofstarch were well mixed and then mixed with a starch paste prepared fromthe remaining 30 g. of starch and about nine times its weight of hotwater. The resulting mass was granulated through a No. 10 mesh B.S.S.sieve and dried at 40 to 50 C. The dried granules were passed through aNo. 12 mesh B.S.S. sieve and then well mixed with the magnesiumstearate. The resulting granules were then compressed so that eachtablet weighed 600 mg. and contained 400 mg. of1:3-benzoxazine-2:4-dione. The tablet may be scored so that half orquarter of this dosage may be taken.

Example 2 may be scored so that half or quarter of this dosage may betaken.

Example 3 g. of 1:3-benzoxazine-2z4-dione were mixed with l g. ofcalcium phosphate and the resulting powdered mixture was filled intohard gelatin capsules such that each contained 100 mg. of the activecomponent.

Example 4 100 g. of 1:3-benzoxazine-2z4-dione were milled with 25 g. ofliquid paraifin and mg. of the resulting suspension were filled intoeach soft gelatin capsule which then contained 100 mg. of the activecomponent.

Example 5 100 g. of 1:3-benzoxazine-2z4-dione were mixed with l g. ofcalcium phosphate and the resulting powdered mixture was filled intocachets such that each contained 400 mg. of the active component.

Example 6 100 g. of 1:3-benzoxazine-2z4-dione were well mixed with 100g. of lactose, the resulting powder being packaged so that eachindividual packaged powder contained 400 mg. of1:3-benzoxazine-2z4-dione.

Example 7 A suspension containing 100 mg. of 1:3-benzoxazine- 2:4dioneper 4 ml. teaspoonful was prepared from the following:

1:3-benzoxazine-2z4-dione g 2.5 Methyl cellulose, powdered, 450 1 g 1.0Syrup B.P. ml 30.0 Methyl hydroxybenzoate g 0.1 Propyl hydroxybenzoateg- 0.02 Orange oil ml 0.5 Citric acid 0.1 Polyoxyethylene sorbitanmonolaurate g 3.0 Glycerin ml 5 Distilled water to ml 100 1 This figurerepresents the viscosity in centipoises of a 2% solution in water at 20C. as determined in an Ostwald viscometer or a falling sphere viscometer(B.S.S.188 21937) The methyl and propyl hydroxybenzoates were dissolvedby boiling in 35 ml. of distilled water and the methyl cellulose wasdispersed by stirring in the resulting solution when cooled. The citricacid was dissolved in the resulting mucilage, to which the syrup wasthen added and mixed therein. The resulting mixture was then trituratedwith the 1:3-benzoxazine-2z4-dione to form a smooth suspension.

The orange oil was mixed with the Polyoxyethylene sorbitan monolaurateto form a mixture to which the glycerin was added. The resulting mixturewas then added to the abovementioned suspension. Distilled water wasthereafter added to volume and the mixture stirred to form a homogeneoussuspension.

Example 8 Suppositories containing 200 mg. of 1:3-benzoxazine- 2:4-dionein each were prepared as follows:

20 g. of l:3-benzoxazine-2:4-dione were finely powdered and trituratedwith 80 g. of melted oil of theobroma to form an even suspension. Themolten suspension at approximately 45 C. was poured into lubricatedsuppository moulds of nominal 1 g. capacity to produce suppositorieseach containing 200 mg. of 1:3-benzoxazine-2z4- dione.

Example 9 Tablets each containing 100 mg. of 1:3-benzoxazine- 2:4-dioneand 324 mg. of aspirin were prepared from the following:

A: G. 1:3-benzoxazine-2z4-dione 100 Lactose 20 Maize starch, dried 30Aspirin 324 Maize starch, dried 64.8 Talc, purified 21.2

broken down and passed through a No. 10 mesh B.S.S.

sieve.

The granules A and slugs B were well mixed and the talc, passed througha No. 60 mesh B.S.S. sieve, was added to the mixed granules. After againmixing, the granules were compressed into tablets each weighing 560 mg.and containing mg. of 1:3-benzoxazine-2z4-dione and 324 mg. of aspirin.

Example 10 Tablets were prepared from the following:

1 3-benzoxazine-2z4-dione 50 Phenacetin Caffeine 30 Lactose 88 Maisestarch (dried) 80 Magnesium stearate 2 The 1:3-benzoxazine-2z4-dione,phenacetin, caffeine, lactose and 60 g. of the maize starch were wellmixed and then massed together with starch paste prepared from theremaining 20 g. of maize starch and water. The resulting mixture wasgranulated through a No. 10 mesh B.S.S. sieve and dried at 40 to 50 C.The dried granules were passed through a No. 12 mesh B.S.S. sieve andwell mixed with the magnesium stearate which had previously been passedthrough a No. 60 mesh B.S.S. sieve. The resulting granules were thencompressed so that each tablet weighed 400 mg. and contained 50 mg.l:3-benzoxazine-2z4-dione, 150 mg. phenacetin and 30 mg. caffeine.

Example 11 Tablets were prepared from the following:

G. l:3-benzoxazine-2:4-dione 50 Lactose 10 Maize starch (dried) 14.9Magnesium stearate 0.1

The 1:3-benzoxazine-2:4-dione, lactose and 11.0 g, of the starch werewell mixed and then mixed with a starch paste prepared from theremaining 3.9 g. of starch and water. The resulting mass was granulatedthrough a No. 10 mesh B.S.S. sieve and dried at 40 C. to 50 C. The driedgranules were passed through a No, 16 mesh B.S.S. sieve and were thenWell mixed with the magnesium stearate. The resulting granules were thencompressed so that each tablet weighed 75 mg. and contained 50 mg. of1:3-benzoxazine-2:4-dione. The tablets may be scored so that half or aquarter of this dosage may be taken.

I claim:

1. A method of obtaining an analgesic effect which comprisesadministering an analgesically effective nontoxic quantity of a compoundselected from the group consisting of 1:3-benzoxazine-2:44iione andpharmacologically acceptable alkali metal salts thereof,

2. A method in accordance with claim 1 in which the compound isadministered in a dose which comprises from 10 to 1000 milligrams of thecompound.

3. A method in accordance with claim 1 in which the compound isadministered orally.

4. A pharmaceutical preparation in dosage unit form adapted foradministration to obtain an analgesic effect, comprising, per dosageunit, an analgesically-effective nontoxic amount within the range fromabout 10 to about 1000 milligrams of at least one compound selected fromthe group consisting of 1:3-benzoxazine-2z4-dione and pharmacologicallyacceptable alkali metal salts thereof, and a pharmaceutical diluent.

5 6 5. A pharmaceutical preparation in accordance with OTHER REFERENCESclaim 4 in a form adapted for oral administration.

6. A pharmaceutical preparation in accordance with Wolfe et Chem Abst"20570d 1959' claim 5 in the form ofatablet Comanducci, Chem. Abst., vol.18, p. 1658 1924. 7. A pharmaceutical preparation in accordance withShapiro 6t 's Val P- 28/1014, 1957 claim 4 comprising phenacetin and atleast one compound Wilson, American Drug Index, p, 5-9, 1960.

selected from the group consisting of caffeine and codeine.

ALBERT T. MEYERS, Primary Examiner.

References (med 3. FRIEDMAN, Assistant Examiner. UNITED STATES PATENTS10 2,943,087 6/1960 Obnacker 260244

1. A METHOD OF OBTAINING AN ANALGESIC EFFECT WHICH COMPRISESADMINISTERING AN ANALGESICALLY EFFECTIVE NONTOXIC QUANTITY OF A COMPOUNDSELECTED FROM THE GROUP CONSISTING OF 1:3-BENZOXAZINE-2:4-DIONE ANDPHARMACOLOGICALLY ACCEPTABLE ALKALI METAL SALTS THEREOF.